Progress in the Development of Inhibitors Targeting Discoidal Structural Domain Receptor Kinases

Abstract: Discoidal structural domain receptor kinases (DDRs) are novel receptor tyrosine kinases that have been discovered in recent years. Scientists have demonstrated molecularly that DDR1 and DDR2 are located upstream of numerous cellular signaling pathways, and are essential for regulating numerous cellular life behaviors. They are particularly significant in cancer therapy, suggesting that DDRs are highly promising targets. In recent years, the heterogeneity and clonal evolution of tumor cells, as well as the overexpression of multidrug-resistant proteins, have reduced the efficacy of many targeted anticancer drugs. Therefore, the discovery of novel targets and the development of corresponding inhibitors are crucial for addressing the growing problem of drug resistance in cancer cells. Currently developed small-molecule DDR inhibitors suffer from low kinase selectivity, poor physicochemical properties, poor drug-metabolism properties, etc., and there are still no selective small-molecule DDR inhibitors on the market. This study reviews research progress on DDRs kinases, systematically outlines the development process of single-target and dual-target smallmolecule inhibitors for DDR1 and DDR2, and presents insights and implications for future research based on empirical evidence, aiming to provide a reference for subsequent studies.